WO2007085833A2 - Derives de pyrimidine - Google Patents

Derives de pyrimidine Download PDF

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Publication number
WO2007085833A2
WO2007085833A2 PCT/GB2007/000251 GB2007000251W WO2007085833A2 WO 2007085833 A2 WO2007085833 A2 WO 2007085833A2 GB 2007000251 W GB2007000251 W GB 2007000251W WO 2007085833 A2 WO2007085833 A2 WO 2007085833A2
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Prior art keywords
alkyl
hydrogen
group
heterocyclyl
halo
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PCT/GB2007/000251
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English (en)
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WO2007085833A3 (fr
Inventor
Jason Grant Kettle
Jon Read
Andrew Leach
Bernard Christophe Barlaam
Richard Ducray
Christine Marie Paul Lambert-Van Der Brempt
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Astrazeneca Ab
Astrazeneca Uk Limited
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Priority to US12/161,766 priority Critical patent/US20110046108A1/en
Priority to JP2008551870A priority patent/JP2009524632A/ja
Priority to BRPI0707284-8A priority patent/BRPI0707284A2/pt
Priority to AU2007209126A priority patent/AU2007209126B2/en
Priority to NZ569763A priority patent/NZ569763A/en
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Priority to EP07700405A priority patent/EP1981856A2/fr
Priority to CA002640375A priority patent/CA2640375A1/fr
Publication of WO2007085833A2 publication Critical patent/WO2007085833A2/fr
Publication of WO2007085833A3 publication Critical patent/WO2007085833A3/fr
Priority to IL192610A priority patent/IL192610A0/en
Priority to NO20083059A priority patent/NO20083059L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel pyrimidine derivatives, to pharmaceutical compositions containing these derivatives and to their use in therapy, in particular in the prevention and treatment of solid tumour disease in a warm blooded animal such as man.
  • a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene i.e. a gene which, on activation, leads to the formation of malignant tumour cells (Bradshaw, Mutagenesis 1986, 1, 91).
  • oncogenes give rise to the production of peptides which are receptors for growth factors. Activation of the growth factor receptor complex subsequently leads to an increase in cell proliferation.
  • oncogenes encode tyrosine kinase enzymes and that certain growth factor receptors are also tyrosine kinase enzymes (Yarden et al, Ann. Rev. Biochem., 1988, 57, 443; Larsen et al, Ann. Reports in Med. Chem.. 1989, Chpt. 13).
  • Receptor tyrosine kinases are important in the transmission of biochemical signals which initiate a variety of cell responses including proliferation, survival and migration.
  • EGF epidermal growth factor
  • Various classes of receptor tyrosine kinases are known (Wilks, Advances in Cancer Research, 1993, 60 43-73) and are classified on the basis of the growth factor family to which they bind.
  • This classification includes Class I receptor tyrosine kinases comprising the EGF family of receptor tyrosine kinases such as the EGF, TGF ⁇ , Neu and erbB receptors, Class II receptor tyrosine kinases comprising the insulin family of receptor tyrosine kinases such as the insulin and IGFl receptors and insulin-related receptor (IRR) and Class III receptor tyrosine kinases comprising the platelet-derived growth factor (PDGF) family of receptor tyrosine kinases such as the PDGF ⁇ , PDGF ⁇ and colony-stimulating factor 1 (CSFl) receptors.
  • EGF EGF family of receptor tyrosine kinases
  • TGF ⁇ TGF ⁇
  • Neu and erbB receptors Class II receptor tyrosine kinases comprising the insulin family of receptor tyrosine kinases such as the insulin and IGFl receptors and insulin-related receptor (IRR)
  • Eph family is the largest known family of receptor tyrosine kinases, with 14 receptors and 8 cognate ephrin ligands identified in mammals (Reviewed in Kullander and Klein, Nature Reviews Molecular Cell Biology. 2002, 3, 475-486).
  • the receptor family is further sub-divided into two sub-families, which are defined largely by the homology of the extracellular domains and their affinity towards a particular ligand type.
  • all Ephs contain an intracellular tyrosine kinase domain and an extracellular Ig-like domain with a cysteine-rich region with 19 conserved cysteines and two fibronectin type III domains.
  • EphAl-8 The A-class of Ephs consists of 8 receptors, termed EphAl-8, which generally bind to their cognate ephrinA class of ligands, termed ephrinAl-5.
  • EphBl-6 6 receptors, termed EphBl-6, which bind to their cognate ephrinB ligands, termed ephrinBl-3.
  • Eph receptor ligands are unusual and different to most other receptor tyrosine kinase ligands in that they are also tethered to cells, via a glycosylphosphatidylinositol linker in ephrinA ligands or an integral transmembrane region in ephrinB ligands.
  • Binding of ephrin ligand to the Eph partner induces a conformational change within the Eph intracellular domain that enables phosphorylation of tyrosine residues within an auto- inhibitory juxtamembrane region, which relieves this inhibition of catalytic site and enables additional phosphorylation to stabilise the active conformation and generate more docking sites for downstream signalling effectors.
  • Eph/ephrin signalling can regulate other cell responses such as proliferation and survival.
  • Eph receptor signalling may contribute to tumourigenesis in a wide variety of human cancers, either on tumour cells directly or indirectly via modulation of vascularisation.
  • Eph receptors are over- expressed in various tumour types (Reviewed in Surawska et ah, Cytokine & Growth Factor Reviews, 2004, 1_5, 419-433, Nakamoto and Bergemann, Microscopy Res and Technique, 2002, 59, 58-67); EphA2 and other EphA receptor levels are elevated in diverse tumours such as leukemias, breast, liver, lung, ovarian and prostate.
  • EpIiB receptors including EphB4 are up-regulated in tumours such as neuroblastomas, leukemias, breast, liver, lung and colon.
  • tumours such as neuroblastomas, leukemias, breast, liver, lung and colon.
  • over- expression of Eph receptors on cancer cells is able to confer tumourigenic phenotypes such as proliferation and invasion, consistent with the speculated role in oncogenesis.
  • EphA2 over-expression in MCF-IOA mammary epithelial cells is sufficient to cause tumourigenesis (Zelinski et al, Cancer Res., 2001, 61 . , 2301-2306).
  • Inhibition of EphA2 function with therapeutic antibodies (Coffman et al, Cancer Res., 2003, 63, 7907-7912) or interfering-RNA (Landen et al, Cancer Res., 2005, H, 6910-6918) has been demonstrated to inhibit tumour growth in in vivo xenograft models.
  • EphA2 and EphB4 may contribute to tumour vascularisation
  • EphB4 (Reviewed in Brantley-Sieders et ah, Current Pharmaceutical Design, 2004, JjO, 3431- 3442, Cheng et al., Cytokine and Growth Factor Reviews, 2002, 13., 75-85).
  • EphA2 and EphB4 are expressed on endothelial cells.
  • Transgenic studies have shown that disruption of EphB4 (Gerety et al., Molecular Cell, 1999, 4, 403-414) or its ligand ephrinB2 (Wang et al, CeJl, 1998, 93, 741-753) causes embryonic lethality associated with vascular modelling defects consistent with a critical role in vessel development.
  • EphB4 activation stimulates endothelial cell proliferation and migration in vitro (Steinle et ⁇ /., J. Biol. Chem., 2002, 277, 43830-43835).
  • EphB4 signalling using soluble extracellular-domains of EphB4 have been shown to inhibit tumour growth and angiogenesis in in vivo xenograft studies (Martiny-Baron et al., Neoplasia, 2004, 6, 248-257, Kertesz et al, Blood, 2005, Pre-published online).
  • soluble EphA2 inhibited tumour vascularisation in a variety of in vivo models (Brantley et al, Oncogene, 2002, 21 . , 7011-7026, Cheng et al, Neoplasia, 2003, 5, 445-456).
  • an inhibitor of Eph receptors should be of value as a selective inhibitor of the proliferation and survival of tumour cells by either targeting tumour cells directly or via effects on tumour vascularisation.
  • such inhibitors should be valuable therapeutic agents for the containment and/or treatment of tumour disease.
  • tyrosine kinases belong to the class of nonreceptor tyrosine kinases which are located intracellularly and are involved in the transmission of biochemical signals such as those that influence tumour cell motility, dissemination and invasiveness and subsequently metastatic tumour growth (Ullrich et al, CeJL 1990, 6]_, 203-212, Bolen et al, FASEB J.. 1992, 6, 3403-3409, Brickell et al, Critical Reviews in Oncogenesis, 1992, 3, 401-406, Bohlen et al, Oncogene, 1993, 8, 2025-2031, Courtneidge et al, Semin.
  • non-receptor tyrosine kinases including the Src family such as the Src, Lyn and Yes tyrosine kinases, the AbI family such as AbI and Arg and the Jak family such as Jak 1 and Ty k 2.
  • Src family of non-receptor tyrosine kinases are highly regulated in normal cells and in the absence of extracellular stimuli are maintained in an inactive conformation.
  • some Src family members for example c-Src tyrosine kinase, are frequently significantly activated (when compared to normal cell levels) in common human cancers such as gastrointestinal cancer, for example colon, rectal and stomach cancer (Cartwright et ⁇ l, Proc. Natl. Acad. ScL USA.
  • NSCLCs including adenocarcinomas and squamous cell cancer of the lung (Mazurenko et al.. European Journal of Cancer, 1992, 28, 372-7), bladder cancer (Fanning et ⁇ l., Cancer Research, 1992, 52, 1457-62), oesophageal cancer (Jankowski et al, Gut, 1992, 33, 1033- 8), cancer of the prostate, ovarian cancer (Wiener et al, Clin. Cancer Research, 1999, 5, 2164-70) and pancreatic cancer (Lutz etat., Biochem. and Biophvs. Res. Comm., 1998, 243, 503-8).
  • Src family of non- receptor tyrosine kinases it is expected that its widespread prevalence will be established.
  • c-Src non-receptor tyrosine kinase is to regulate the assembly of focal adhesion complexes through interaction with a number of cytoplasmic proteins including, for example, focal adhesion kinase and paxillin.
  • cytoplasmic proteins including, for example, focal adhesion kinase and paxillin.
  • c-Src is coupled to signalling pathways that regulate the actin cytoskeleton which facilitates cell motility.
  • colon tumour progression from localised to disseminated, invasive metastatic disease has been correlated with c-Src non-receptor tyrosine kinase activity (Brunton et al, Oncogene, 1997, JA, 283-293, Fincham et al, EMBO J, 1998, 17, 81 -92 and Verbeek et ah, Exp. Cell Research. 1999, 248, 531-537).
  • an inhibitor of such non-receptor tyrosine kinases should be of value as a selective inhibitor of the motility of tumour cells and as a selective inhibitor of the dissemination and invasiveness of mammalian cancer cells leading to inhibition of metastatic tumour growth.
  • an inhibitor of such non-receptor tyrosine kinases should be of value as an anti-invasive agent for use in the containment and/or treatment of solid tumour disease.
  • pyrimidines are useful in the inhibition of EphB4 and, in some cases, EphA2 and Src kinase as well. Such pyrimidines are therefore are useful in therapy, where such enzymes are implicated.
  • R 1 is selected from hydrogen, C h alky L C 2 _ 6 alkenyl 5 or C 2-6 alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted by one or more substituents selected from cyano, nitro, -OR 2 , -NR 2a R 2b , -C(O)NR 2a R 2b , -N(R 2a )C(O)R 2 , halo or haloC 1-4 alkyl (such as trifluoromethyl), where R 2 , R 2a and R 2b are selected from hydrogen or Ci -6 alkyl such as methyl, or R 2a and R 2b together with the nitrogen atom to which they are attached may form a 5 or 6-membered heterocyclic ring, which optionally contains an additional heteroatom selected from N, O or S;
  • ring A is fused 5 or 6-membered carbocyclic or heterocyclic ring, which is saturated or unsaturated, and is optionally substituted on any available carbon atom by one or more substituent groups selected from halo, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, -S(O) Z -C 1- 6 alkyl (where z is 0, 1 or 2), or -NR a R b (where R a and R b are each independently selected from hydrogen, Chalky 1, or Ci-4alkylcarbonyl), and where any nitrogen atoms in the ring are optionally substituted by a C 1-6 alkyl or Ci -6 alkylcarbonyl; n is O, 1, 2 or 3
  • each group R 3 is independently selected from halo, trifluoromethyl, cyano, nitro or a group of sub-formula (i) :
  • X 1 is selected from a direct bond or O, S, SO, SO 2 , OSO 2 , NR 13 , CO, CH(OR 13 ), CONR 13 , N(R 13 )C0, SO 2 N(R 13 ), N(R 13 )SO 2 , C(R 13 ) 2 O, C(R 13 ) 2 S, C(R 13 ) 2 N(R 13 ) and N(R 13 )C(R 13 ) 2 , wherein R 13 is hydrogen or C 1-6 alkyl and R 11 is selected from hydrogen, Ci -6 alkyl, C 2- salkenyl, C 2- 8alkynyl, C 3 _ 8 cycloalkyl, aryl or heterocyclyl, C 3-8 cycloalkylC 1-6 alkyl, arylCi -6 alkyl or heterocyclylC 1-6 alkyl, any of which may be optionally substituted with one or more groups selected from halo,
  • R 4 is a group of sub-formula (iii)
  • R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from: (a) hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, C 1-6 alkyl, C 2- galkenyl, C 2 , 8 alkynyl, aryl, C 3-12 carbocyclyl, aryl-C 1-6 alkyl, heterocyclyl (including heteroaryl), heterocyclyl-Ci-galkyl (including heteroaryl-C).
  • any aryl, C 3-12 carbocyclyl, aryl-C 1-6 alkyl, heterocyclyl (including heteroaryl), heterocyclyl-d- ⁇ alkyl (including heteroaryl-Ci- ⁇ alkyl) groups are optionally substituted on any available carbon atoms by halo, hydroxy, cyano, amino, C 1-6 alkyl, hydroxyC[ -6 alkyl, Ci -6 alkoxy, C 1-6 alkylcarbonyl, N-Ci- 6 alkylamino, or N,N-diCi -6 alkylamino, and any nitrogen atoms present in a heterocyclyl group may, depending upon valency considerations, be substituted by a group selected from hydrogen, Ci -6 alkyl or Ci -6 alkylcarbonyl, and where any sulphur atoms may be optionally oxidised to a sulphur oxide; (b) a group of sub-formula (iv)
  • X 2 is selected from O, NR 16 , S 5 SO 5 SO 2 , OSO 2 , CO, C(O)O, OC(O), CH(OR 16 ), CON(R 16 ), N(R 16 )C0, -N(R 16 )C(O)N(R 16 )-, -N(R 16 )C(0)0-, SON(R 16 ), N(R 16 )SO, SO 2 N(R 16 ), N(R 16 )SO 2 , C(R 16 ) 2 O, C(R 16 ) 2 S and
  • R 14 is hydrogen, C 1-6 alkyl, trifluoromethyl, C 2-8 alkenyl, C 2- galkynyl, aryl, C 3-12 carbocyclyl, aryl-C 1-6 alkyl, or a 4- to 8-membered mono or bicyclic heterocyclyl ring (including 5 or 6 membered heteroaryl rings) or 4- to 8-membered mono or bicyclic heterocyclyl-Ci -6 alkyl groups (including 5 or 6 membered heteroaryl - C 1-6 alkyl groups) and wherein any aryl, C 3-12 carbocyclyl, aryl-Ci -6 alkyl, heterocyclyl (including heteroaryl), heterocyclyl-C[ -6 alkyl (including heteroaryl- C 1-6 alkyl) groups are optionally substituted on any available carbon atoms by oxo, halo, cyano, amino, C 1-6 alkyl, hydroxyCi -6 alkyl, Ci -6 alk
  • C 1-6 alkylamino, or N,N-diC 1-6 alkylamino and any nitrogen atoms present in the heterocyclyl moieties may, depending upon valency considerations, be substituted by a group selected from hydrogen, C 1-6 alkyl or C 1-6 alkylcarbonyl, and where any sulphur atoms may be optionally oxidised to a sulphur oxide; (c) a group of sub-formula (v):
  • X 3 is a direct bond or is selected from O, NR 17 , S, SO, SO 2 , OSO 2 , CO, C(O)O, OC(O), CH(OR 17 ), CON(R 17 ), N(R 17 )C0, -N(R 17 )C(O)N(R 17 )-, -N(R I7 )C(0)0-, SO 2 N(R 17 ), N(R 17 )SO 2 , C(R 17 ) 2 O, C(R 17 ) 2 S and N(R 17 )C(R 17 ) 2 , where each R 17 is independently selected from hydrogen or Ci ⁇ alkyl;
  • R 15 is a d- ⁇ alkylene, C 2-6 alkenylene or C 2-6 alkynylene, arylene, C 3-12 carbocyclyl, heterocyclyl (including heteroaryl), any of which may be optionally substituted by one or more groups selected from halo, hydroxy, C 1-6 alkyl, C ⁇ alkoxy, cyano, amino, C 1-6 alkylamino or di-(Ci -6 alkyl)arnmo, Z is halo, trifluoromethyl, cyano, nitro, aryl, C 3-12 carbocyclyl or heterocyclyl
  • X 4 is selected from O, NR 19 , S, SO, SO 2 , OSO 2 , CO, C(O)O, OC(O),
  • R 19 is independently selected from hydrogen or Ci- ⁇ alkyl; and R 18 is selected from hydrogen, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 3-12 carbocyclyl, aiyl-C 1-6 alkyl, heterocyclyl (including heteroaryl) or heterocyclyl-C 1-6 alkyl (including heteroaryl-
  • Ci- ⁇ alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halo, Ci -6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl and C 1-6 alkoxy, and wherein any heterocyclyl group within R 18 optionally bears 1 or 2 oxo substituents; or (d) R 5 and R 6 , R 6 and R 7 , R 7 and R 8 or R 8 and R 9 are joined together to form a fused 5, 6 or 7-membered ring, wherein said ring is unsaturated or partially or fully saturated and is optionally substituted on any available carbon atom by halo, Ci- 6 alkyl, hydroxyC 1-6 alkyl, amino, N-C 1-6 alkylamino, or N,N-diCi -6 alkylamino, and said ring may contain one or more heteroatoms selected from oxygen, sulphur or nitrogen, where sulphur atoms may be optionally oxidised
  • R 1 is selected from hydrogen or optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl or optionally substituted C 2-6 alkynyl;
  • ring A is fused 5 or 6-membered carbocyclic or heterocyclic ring which is optionally substituted on a carbon atom by one or more halo groups or C 1-6 alkyl groups, and where any nitrogen atoms in the ring are optionally substituted by a Ci. 6 alkyl or C- i -6 alkylcarbonyl;
  • n 0, 1, 2 or 3
  • each group R is independently selected from halo, trifluoromethyl, cyano, nitro or a group of sub-formula (i) : -X 1 -R 11 (i) where X 1 is selected from a direct bond or O, S, SO, SO 2 , OSO 2 , NR 13 , CO, CH(OR 13 ), CONR 13 , N(R 13 )CO, SO 2 N(R 13 ), N(R 13 )SO 2 , C(R 13 ) 2 O, C(R 13 ) 2 S, C(R 13 ) 2 N(R 13 ) and N(R 13 )C(R 13 ) 2 , wherein R 13 is hydrogen or C 1-6 alkyl and R 11 is selected from hydrogen, Ci -6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 Cy cloalkyl, aryl or heterocyclyl, C 1-6 alkylC 3-8 cycloalkyl, Cj -6 alkyla
  • R 4 is an optionally substituted phenyl ring, wherein one or more adjacent substituents may be joined together to form a fused bicyclic or tricyclic ring; or a pharmaceutically acceptable salt thereof.
  • optically active or racemic forms by virtue of one or more asymmetric carbon atoms
  • the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
  • tautomerism may affect any heterocyclic groups that bear 1 or 2 oxo substituents.
  • present invention includes in its definition any such tautomeric form, or a mixture thereof, which possesses the above-mentioned activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings or named in the Examples.
  • references to individual alkyl groups such as "propyl” are specific for the straight-chain version only
  • An analogous convention applies to other generic terms, for example (l- ⁇ C)alkoxy includes methoxy, ethoxy and isopropoxy
  • (l- ⁇ C)alkylamino includes methylamino, isopropylamino and ethylamino
  • di-[(l-6Calkyl]amino includes dimethylamino, diethylamino and N-methyl-N-isopropylamino.
  • alkenyl or alkynyl groups may be straight chain or branched.
  • aryl refers to phenyl or naphthyl, particularly phenyl.
  • halo refers to fluoro, chloro, bromo, or iodo.
  • heterocyclyl or “heterocyclic ring”, unless otherwise defined herein, refers to saturated, partially saturated or unsaturated, mono, bicyclic or tricyclic rings containing 3-15 atoms, of which at least one atom is chosen from nitrogen, sulphur or oxygen. These groups may, unless otherwise specified, be carbon or nitrogen linked. In addition, or a ring sulphur atom may be optionally oxidised to form the S-oxides.
  • a “heterocyclyl” or “heterocyclic ring” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 3-12 atoms, and especially 4 to 10 atoms, of which at least one atom is chosen from nitrogen, sulphur or oxygen.
  • Monocyclic “heterocyclyls” or “heterocyclic rings” suitably contain from 3-7 ring atoms, in particular 5 or 6 ring atoms.
  • heterocyclyl examples and suitable values of the term "heterocyclyl” are thienyl, piperidinyl, morpholinyl, furyl, thiazolyl, pyridyl, imidazolyl, 1,2,4-triazolyl, thiomorpholinyl, coumarinyl, pyrimidinyl, phthalidyl, pyrazolyl, pyrazinyl, pyridazinyl, benzothienyl, benzimidazolyl, tetrahydrofuryl, [l,2,4]triazolo[4,3-a]pyrimidinyl, piperidinyl, indolyl, indazolyl, benzothiazolyl, benzoxazolyl, 1,3-benzodioxolyl, pyrrolidinyl, pyrrolyl, quinolinyl, isoquinolinyl, isoxazolyl, benzofuranyl, 1,2,3
  • Heterocyclyl groups may be non-aromatic or aromatic in nature. Aromatic heterocyclyl groups are specifically referred to as heteroaryl. Heteroaryl groups are totally unsaturated, mono or bicyclic rings containing 3-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked. Suitably “heteroaryl” refers to a totally unsaturated, monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 8 - 10 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked.
  • heteroaryl examples and suitable values of the term "heteroaryl” are thienyl, furyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl, triazolyl, pyranyl, indolyl, pyrimidyl, pyrazinyl, pyridazinyl, benzothienyl, pyridyl and quinolyl.
  • R 1 is an optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl or optionally substituted C 2-6 alkynyl
  • optional substituents are suitably selected from cyano, -OR 2 , -NR 2a R 2b , -C(O)NR 2a R 2b , or -N(R 2a )C(O)R 2 , halo or haloC ⁇ alkyl such as trifluoromethyl, where R 2 , R 2a and R 2b are selected from hydrogen or Ci -6 alkyl such as methyl, or R 2a and R 2b together with the nitrogen atom to which they are attached may form a heterocyclic ring which optionally contains an additional heteroatom.
  • R 1 is hydrogen.
  • n is 0, 1 , or 2.
  • n is 0 or 1.
  • n is 1.
  • a substituent R 3 is suitably positioned on the available ortho- carbon atom of the ring, forming a compound of formula (IA)
  • R 3a is a group R 3 as defined herein, and in particular is halo, and m is 0, 1 or 2.
  • a groups are set out below, and include for example groups A' as defined below.
  • R 3 or R 3a groups are groups selected from halo, trifiuoromethyl, cyano, hydroxy, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl and C 1-6 alkoxy.
  • R 3 or R 3a may be selected from chloro, fluoro, bromo, trifiuoromethyl, cyano, hydroxy, methyl, ethyl, ethynyl, methoxy and ethoxy.
  • R 3 or R 3a is halo, such as bromo, chloro or fluoro, and in particular chloro.
  • n is 1 and R 3 or R 3a is halo such as chloro.
  • a group A includes more than one group R 20 or R , at least one such group is hydrogen.
  • groups R 20 include hydrogen, methyl, ethyl or methylcarbonyl, in particular hydrogen.
  • groups R 22 include hydrogen, chloro, fluoro, methyl or ethyl, in particular hydrogen.
  • Ring A is a fused five-membered ring.
  • R 20 include hydrogen, methyl, and acetyl.
  • R 20 is hydrogen.
  • Ring A includes one nitrogen atom.
  • Ring A may also include two nitrogen atoms.
  • Ring A is a group of formula -0-CH 2 -O- or -0-CF 2 -O-, in particular -0-CH 2 -O-.
  • examples of compounds of formula (I) are compounds of formula
  • R , R , R and n are as defined.
  • Particular examples of optionally substituted phenyl groups R 4 are groups of sub- formula (iii)
  • R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from:
  • X 2 is selected from O, NR 16 S, SO, SO 2 , OSO 2 , CO, C(O)O, OC(O), CH(OR 16 ), CON(R 16 ), N(R 16 )C0, -N(R 16 )C(O)N(R 16 )-, -N(R 16 )C(O)O- SO 2 N(R 16 ), N(R 16 )SO 2 , C(R 16 ) 2 O, C(R 16 ) 2 S andN(R 16 )C(R 16 ) 2 , where each R 16 is independently selected from hydrogen or Ci -6 alkyl, R 14 is hydrogen, Ci -6 alkyl, trifluoromethyl, C 2- galkenyl, C 2- galkynyl, aryl, C 3-I2 carbocyclyl, aryl-Ci_ 6 alkyl, heterocyclyl (including heteroaryl) or heterocyclyl- Ci -6 alkyl (
  • Z is halo, trifluoromethyl, cyano, nitro, aryl, C 3-12 carbocyclyl or heterocyclyl (including heteroaryl) which optionally bears 1 or 2 substituents, which may be the same or different, selected from halo, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl and Ci -6 alkoxy and wherein any heterocyclyl group within Z optionally bears 1 or 2 oxo substituents, or Z is a group of sub-formula (vi)
  • X 4 is selected from O, NR 19 S, SO, SO 2 , OSO 2 , CO, C(O)O, OC(O),
  • each R 19 is independently selected from hydrogen or Ci -6 alkyl; and R 18 is selected from hydrogen, Ci -6 alkyl, C 2-8 alkenyl, C 2- galkynyl, aryl, C 3- I 2 carbocyclyl, aryl-Ci -6 alkyl, heterocyclyl (including heteroaryl) or heterocyclyl-Ci- ⁇ alkyl (including heteroaryl-
  • Ci -6 alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halo, Ci -6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl and Ci -6 alkoxy, and wherein any heterocyclyl group within R 18 optionally bears 1 or 2 oxo substituents; or (d) R 5 and R 6 , R 6 and R 7 , R 7 and R 8 or R 8 and R 9 are joined together to form a fused ring, which is optionally substituted, and which may contain one or more heteroatoms selected from oxygen, sulphur or nitrogen, where sulphur atoms may be optionally oxidised to a sulphur oxide, where any CH 2 groups may be substituted by a C(O) group, and where nitrogen atoms, depending upon valency considerations, may be substituted by a group R 21 , where R 21 is selected from hydrogen, C 1-6 alkyl or C 1-6 alkylcarbonyl.
  • At least one of R 5 , R 6 , R 7 , R 8 and R 9 is other than hydrogen. In a particular embodiment, at least one of R 6 , R 7 or R 8 is other than hydrogen.
  • R 5 , R 6 , R 7 , R 8 and R 9 where these are other than hydrogen include halo, trifluoromethoxy, cyano, C 2- 8alkynyl, heterocyclyl , a group of sub-formula (iv)
  • X 2 is selected from O, NR 16 , SO 2 , CON(R 16 ), N(R 16 )C0, SO 2 N(R 16 ), N(R 16 )SO 2 , where each R 16 is independently selected from hydrogen or C 1-6 alkyl, and R 14 is hydrogen, Ci- 6 alkyl or trifluoromethyl, or a group of sub-formula (v) :
  • X 3 is a direct bond or is selected from O, CON(R 17 ), N(R 17 )C0, SO 2 N(R 17 ), N(R 17 )SO 2 , where each R 17 is independently selected from hydrogen or Ci -6 alkyl, and in particular is hydrogen, R 15 is a Ci_ 6 alkylene, and
  • Z is cyano, or heterocyclyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halo or Ci-ealkyl, or Z is a group of sub-formula (vi)
  • X 4 is selected from O, NR 19 CON(R 19 ), N(R 19 )C0, SO 2 N(R 19 ) or N(R 19 )SO 2 , where each R 19 is independently selected from hydrogen or C ⁇ a ⁇ cyl; and R 18 is selected from hydrogen, Ci -6 alkyl, or heterocyclyl.
  • heterocyclic groups for R 5 , R 6 , R 7 , R 8 and R 9 as well as Z include saturated five or six membered rings which contain at least one nitrogen atom and optionally also one or more further heteroatoms selected from oxygen, nitrogen and sulphur. These may be linked either to the phenyl ring in the case of R 5 , R 6 , R 7 , R 8 and R 9 or to the group R 15 in the case of Z via a carbon or nitrogen atom.
  • at least one of R 5 , R 6 , R 7 , R 8 and R 9 or Z is an N-linked heterocyclic group.
  • Particular examples of such groups include pyrrolidine and N-morpholino.
  • groups R 5 , R 6 , R 7 , R 8 or R 9 where these are other than hydrogen include chloro, fluoro, methyl, methoxy, ethoxyethoxy trifluoromethoxy, ethynyl, cyano, hydroxymethyl, hydroxyethyl, cyanomethyl, amido, N-methylamido, N- (2-methoxyethyl)amido, 4-(pyridin-2-ylmethoxy), N-methylmethanesulfonamido, pyrrolidin-1-ylethoxy, morpholino, 2-morpholin-4-ylethoxy, 2-hydroxyethyl)-N- methylsulfonamido, diethylaminoethylamido, 4-methylpiperazin- 1 -yl)ethoxy , fluorobenzyloxy, sulfonamido, methanesulfonamido, methoxyethylsulfonamido,
  • the ring suitably includes at least one heteroatom.
  • a fused ring formed by R 5 and R 6 , R 6 and R 7 , R 7 and R 8 or R 8 and R 9 contains one or two nitrogen atoms or one nitrogen atom and one sulphur atom.
  • the ring includes 5 ring atoms including the carbon atoms to which R 5 and R 6 , R 6 and R 7 , R 7 and R 8 or R 8 and R 9 are attached.
  • Fused rings formed by R 5 and R 6 , R 6 and R 7 , R 7 and R 8 or R 8 and R 9 may carry optional substituents which may be selected from those listed above for R 3 .
  • fused rings include formed by R 5 and R 6 , R 6 and R 7 , R 7 and R 8 or R 8 and R 9 and the phenyl ring to which they are attached include indolyl, indazolyl, indolone and benzothiazolyl.
  • the invention provides a compound of formula (IC)
  • Particular examples of compounds of formula (IC) are compounds of formula (IB) as set out above, and these form a particular aspect of the invention.
  • Particular options for R 1 , R 3 , R 4 n and R 20 in formula (IC) are as set out herein in relation to formula (I).
  • compounds of formula (IB) form a particular aspect of the invention.
  • novel compounds of the invention include, for example, compounds of
  • NR 20 -N N-, where each R 20 is independently selected from hydrogen, C ⁇ aHcyl or d ⁇ alkylcarbonyl, and where each R 22 is independently selected from hydrogen, halo, cyano, hydroxy, Ci -4 alkyl, d ⁇ alkoxy, -S(O) z -Ci -4 alkyl (where z is 0, 1 or 2), or -NR a R b (where R a and R b are each independently selected from hydrogen, Ci -2 alkyl, or C 1-2 alkanoyl).
  • each R 20 is independently selected from hydrogen, C 1-2 alkyl or C 1-2 alkylcarbonyl
  • each R 22 is independently selected from hydrogen, halo, cyano, hydroxy, C ]-2 alkyl, Ci -2 alkoxy, -S(O) 2 -C 1-2 alkyl (where z is 0, 1 or 2), or -NR a R b (where R a and R b are each independently selected from hydrogen, Ci -2 alkyl, or C 1-2 alkanoyl).
  • each R 20 is independently selected from hydrogen, C 1-4 alkyl or C 1-4 alkylcarbonyl
  • each R 22 is independently selected from hydrogen, halo, cyano, hydroxy, Ci -4 alkyl, C 1-4 alkoxy, -S(O) z -C 1-4 alkyl (where z is 0, 1 or 2), or -NR a R b (where R a and R b are each independently selected from hydrogen, C 1-2 alkyl, or Ci -2 alkanoyl).
  • each R 20 is independently selected from hydrogen, C 1-2 alkyl or C ⁇ -2 alkylcarbonyl, and where each R is independently selected from hydrogen, halo, cyano, hydroxy, Ci -2 alkyl, C 1-2 alkoxy, -S(O) z -C 1-2 alkyl (where z is 0, 1 or 2), or -NR a R b (where R a and R b are each independently selected from hydrogen, C 1-2 alkyl, or C 1-2 alkanoyl).
  • R 1 is hydrogen or a C ⁇ alkyl group which is optionally substituted with one or more substituents selected from cyano, -OR 2 , -NR 2a R 2b , -C(O)NR 2a R 2b , or - N(R 2a )C(O)R 2 , halo or haloC 1-4 alkyl (such as trifluoromethyl), where R 2 , R 2a and R 2b are selected from hydrogen or Ci ⁇ alkyl;
  • R 1 is hydrogen or a C 1-2 alkyl group, which is optionally substituted with one or more substituents selected from cyano, -OR 2 , -NR 2a R 2b , -C(O)NR 2a R 2b , or - N(R 2a )C(O)R 2 , halo or haloC 1-4 alkyl (such as trifluoromethyl), where R 2 , R 2a and R 2b are selected from hydrogen or C 1-4 alkyl;
  • R 1 is hydrogen or a C 1-2 alkyl group, which is optionally substituted with one or more substituents selected from cyano, -OR 2 , -NR 2a R 2b , where R 2 , R 2a and R 2b are selected from hydrogen or Ci -2 alkyl;
  • R 1 is hydrogen or a C 1-2 alkyl group
  • R 1 is hydrogen
  • R 1 is a Ci -2 alkyl group, which is optionally substituted with one or more substituents selected from cyano, -OR 2 , -NR 2a R 2b , where R 2 , R 2a and R 2b are selected from hydrogen or Ci -2 alkyl;
  • R 1 is a Ci -2 alkyl group
  • R 1 is methyl
  • n 0, 1, or 2; 18. n is O or l;
  • n O
  • n 1;
  • each group R 3 present is independently selected from halo, trifluoromethyl, cyano, nitro or a group of sub-formula (i) :
  • X 1 is selected from a direct bond or O, S, SO, SO 2 , OSO 2 , NR 13 , CO, CH(OR 13 ), CONR 13 , N(R 13 )CO, SO 2 N(R 13 ), N(R 13 )SO 2 , C(R 13 ) 2 O, C(R 13 ) 2 S, C(R 13 ) 2 N(R 13 ) and N(R 13 )C(R 13 ) 2 , wherein R 13 is hydrogen or C 1-6 alkyl and R 11 is selected from hydrogen, or C 1-6 alkyl, which may be optionally substituted with one or more groups selected from halo, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, and C 1-6 alkoxy;
  • each group R 3 present is independently selected from halo, trifluoromethyl, cyano, nitro or a group of sub-formula (i) :
  • X 1 is selected from a direct bond or O, NR 13 , CO, CONR 13 , N(R 13 )CO, wherein R 13 is hydrogen or C 1-4 alkyl and R 11 is selected from hydrogen or C 1-4 alkyl, which may be optionally substituted with one or more groups selected from halo, cyano, or C 1-4 alkoxy;
  • each group R 3 present is independently selected from halo, trifluoromethyl, cyano, nitro or a group of sub-formula (i) :
  • X 1 is selected from a direct bond or O, CONR 13 , wherein R 13 is hydrogen or C 1-6 alkyl and R 11 is selected from hydrogen or Ci -4 alkyl, which may be optionally substituted with one or more C 1-2 alkoxy groups;
  • each group R 3 present is independently selected from halo or a group of sub- formula (i) :
  • X 1 is selected from a direct bond or O, CONR 13 , wherein R 13 is hydrogen or C 1-6 alkyl and R 11 is selected from hydrogen, Ci -2 alkyl, any of which may be optionally substituted with one or more C 1-2 alkoxy groups;
  • each group R 3 present is independently selected from fluoro, chloro, cyano, -CONH 2 , or Ci -2 alkyl optionally substituted by C 1-2 alkoxy;
  • R 4 is a group of sub-formula (iii)
  • R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from: (a) hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 3-12 carbocyclyl, aryl-Ci -6 alkyl, heterocyclyl
  • heteroaryl including heteroaryl
  • heterocyclyl-C 1-6 alkyl including heteroaryl- Ci -6 alkyl
  • any aryl, C 3-I2 carbocyclyl, aryl-Ci -6 alkyl, heterocyclyl (including heteroaryl), heterocyclyl-Ci -6 alkyl (including heteroaryl-C 1-6 alkyl) groups are optionally substituted on any available carbon atoms by halo, hydroxy, cyano, amino, Ci -6 alkyl, hydroxy C i -6 alkyl,
  • Ci -6 alkoxy, Ci -6 alkylcarbonyl, N-C 1-6 alkylamino, or N,N-diCi-6alkylamino and any nitrogen atoms present in the heterocyclyl moieties may, depending upon valency considerations, be substituted by a group selected from hydrogen, Ci -6 alkyl or Ci -6 alkylcarbonyl, and where any sulphur atoms may be optionally oxidised to a sulphur oxide;
  • X 2 is selected from O, NR 16 , S, SO, SO 2 , OSO 2 , CO, C(O)O, OC(O), CH(OR 16 ), CON(R 16 ), N(R 16 )C0, -N(R 16 )C(O)N(R 16 )-, -N(R 16 )C(0)0-, SON(R 16 ), N(R 16 )SO, SO 2 N(R 16 ), N(R 16 )SO 2 , C(R 16 ) 2 O, C(R 16 ) 2 S andN(R 16 )C(R 16 ) 2 , where each R 16 is independently selected from hydrogen or C 1-6 alkyl,
  • R 14 is hydrogen, C 1-6 alkyl, trifluoromethyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 3-I2 carbocyclyl, aryl-C 1-6 alkyl, or a 4- to 8-membered mono or bicyclic heterocyclyl ring (including 5 or 6 membered heteroaryl rings) or 4- to 8- membered mono or bicyclic heterocyclyl-C 1-6 alkyl groups (including 5 or 6 membered heteroaryl-C 1-6 alkyl groups) and wherein any aryl, C 3-12 carbocyclyl, aryl-C 1-6 alkyl, heterocyclyl (including heteroaryl), heterocyclyl-C 1-6 alkyl (including heteroaryl-C 1-6 alkyl) groups are optionally substituted on any available carbon atoms by oxo, halo, cyano, amino, C 1- 6 alkyl, hydroxyC 1-6 alkyl, Ci -6 alkoxy, Ci
  • R 15 is a C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, arylene, C 3-12 carbocyclyl, heterocyclyl (including heteroaryl), any of which may be optionally substituted by one or more groups selected from halo, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, cyano, amino, Ci -6 alkylamino or di-(Ci -6 alkyl)amino; Z is halo, trifluoromethyl, cyano, nitro, aryl, C 3-12 carbocyclyl or heterocyclyl (including heteroaryl) which optionally bears 1 or 2 substituents, which may be the same or different, selected from halo,
  • X 4 is selected from O, NR 19 , S, SO, SO 2 , OSO 2 , CO, C(O)O, OC(O),
  • R 19 is independently selected from hydrogen or Ci -6 alkyl; and R 18 is selected from hydrogen, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 3-12 carbocyclyl, aryl-Ci- ⁇ alkyl, heterocyclyl (including heteroaryl) or heterocyclyl-C 1-6 alkyl (including heteroaryl-C 1-6 alkyl) which optionally bears 1 or 2 substituents, which may be the same or different, selected from halo, C 1-6 alkyl, C 2-8 alkenyl, C
  • R 6 , R 7 , and R 8 are independently selected from:
  • X 2 is selected from O, NR 16 , S 5 SO 5 SO 2 , OSO 25 CO 5 C(O)O 5 OC(O) 5 CH(OR 16 ), CON(R 16 ), N(R 16 )C0, -N(R 1 ⁇ C(O)N(R 16 )-, -N(R 16 )C(0)0-, SON(R 16 ), N(R 16 )SO, SO 2 N(R 16 ), N(R 16 )SO 2 , C(R 16 ) 2 O, C(R 16 ) 2 S and N(R 16 )C(R 16 ) 2 , where each R 16 is independently selected from hydrogen or C 1-6 alkyl,
  • R 14 is hydrogen, Ci -6 alkyl, trifluoromethyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 3-I2 carbocyclyl, aryl-Ci -6 alkyl, or a 4- to 8-membered mono or bicyclic heterocyclyl ring (including 5 or 6 membered heteroaryl rings) or 4- to 8- membered mono or bicyclic heterocyclyl-Ci -6 alkyl groups (including 5 or 6 membered heteroaryl-Ci -6 alkyl groups) and wherein any aryl, C 3-I2 carbocyclyl, aryl-C 1-6 alkyl, heterocyclyl (including heteroaryl), heterocyclyl-Ci -6 alkyl (including heteroaryl-Ci -6 alkyl) groups are optionally substituted on any available carbon atoms by oxo, halo, cyano, C 1-6 alkyl, hydroxyCi -6 alkyl, C 1-6
  • X 3 is a direct bond or is selected from O, NR 17 , S, SO, SO 2 , OSO 2 , CO, C(O)O, OC(O), CH(OR 17 ), CON(R 17 ), N(R 17 )C0, -N(R l7 )C(O)N(R 17 )-, -N(R 17 )C(0)0-, SO 2 N(R 17 ), N(R 17 )SO 2 , C(R 17 ) 2 O, C(R 17 ) 2 S and N(R 17 )C(R 17 ) 2 , where each R 17 is independently selected from hydrogen or C 1-6 alkyl;
  • R 15 is a Ci -6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, arylene, C 3-I2 carbocyclyl, heterocyclyl (including heteroaryl), any of which may be optionally substituted by one or more groups selected from halo, hydroxy, Ci -6 alkyl, Ci -6 alkoxy, cyano, amino, Ci -6 alkylamino or di-(C 1-6 alkyl)amino;
  • Z is halo, trifluoromethyl, cyano, nitro, aryl, C 3-I2 carbocyclyl or heterocyclyl (including heteroaryl) which optionally bears 1 or 2 substituents, which may be the same or different, selected from halo, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl and Ci -6 alkoxy and wherein any heterocyclyl group within Z optionally bears 1 or 2 oxo substituents, or Z is a group of sub-formula (vi)
  • X 4 is selected from O, NR 19 , S, SO, SO 2 , OSO 2 , CO, C(O)O, OC(O), CH(OR 19 ), CON(R 19 ), N(R 19 )C0, SO 2 N(R 19 ), -N(R 1 ⁇ C(O)N(R 19 )-, -N(R 19 )C(0)0- N(R 19 )SO 2 , C(R 19 ) 2 O, C(R 19 ) 2 S and N(R 19 )C(R 19 ) 2 , where each R 19 is independently selected from hydrogen or C 1-6 alkyl; and R 18 is selected from hydrogen, Cj -6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 3-I2 carbocyclyl, aryl-Ci -6 alkyl, heterocyclyl (including heteroaryl) or heterocyclyl-C 1-6 alkyl (including hetero
  • R 6 and R 7 , or R 7 and R 8 are joined together to form a fused 5-, 6- or 7- membered saturated or unsaturated ring, which is optionally substituted on any available carbon atom by halo, C 1-6 alkyl, hydroxyC 1-6 alkyl, amino, N- C 1-6 alkylamino, or N,N-diC 1-6 alkylamino, and which may contain one or more heteroatoms selected from oxygen, sulphur or nitrogen, where sulphur atoms may be optionally oxidised to a sulphur oxide, where any CH 2 groups may be substituted by a C(O) group, and where nitrogen atoms, depending upon valency considerations, may be substituted by a group R 21 , where R 21 is selected from hydrogen, C 1-6 alkyl or C 1-6 alkylcarbonyl.
  • R 4 is a group of sub-formula (iiia)
  • R 5 R , and R are independently selected from:
  • X 2 is selected from O, NR 16 , S, SO 5 SO 2 , OSO 2 , CO, C(O)O, OC(O), CH(OR 16 ), CON(R 16 ), N(R 16 )CO, SON(R 16 ), N(R 16 )SO, SO 2 N(R 16 ), and N(R 16 )SO 2 , where each R 16 is independently selected from hydrogen or Ci -6 alkyl,
  • R 14 is hydrogen, C 1-6 alkyl, trifluoromethyl, C 2- galkenyl, C 2-8 alkynyl, aryl, C 3- I 2 carbocyclyl, or a 4- to 8-membered mono or bicyclic heterocyclyl ring (including 5 or 6 membered heteroaryl rings) and wherein any aryl, C 3-12 carbocyclyl, heterocyclyl (including heteroaryl) groups are optionally substituted on any available carbon atoms by oxo, halo, cyano, amino, Ci- 6 alkyl, hydroxyC 1-6 alkyl, Ci -6 alkoxy, C 1-6 alkylcarbonyL N-Ci -6 alkylamino, or N,N-diCi.
  • heterocyclyl moieties may, depending upon valency considerations, be substituted by a group selected from hydrogen, Ci_ 6 alkyl or C 1-6 alkylcarbonyl, and where any sulphur atoms may be optionally oxidised to a sulphur oxide;
  • X 3 is a direct bond or is selected from O, NR 17 , S, SO, SO 2 , OSO 2 , CO, C(O)O, OC(O), CON(R 17 ), N(R 17 )CO, SO 2 N(R 17 ), and N(R 17 )SO 2 , where each R 7 is independently selected from hydrogen or Ci -6 alkyl;
  • R 15 is a Ci- ⁇ alkylene, C 2-6 alkenylene or C 2-6 alkynylene, arylene, C 3- I 2 carbocyclyl, heterocyclyl (including heteroaryl), any of which may be optionally substituted by one or more groups selected from halo, hydroxy, Ci -6 alkyl, C 1-6 alkoxy, cyano, amino, Ci- ⁇ alkylamino or di-(Ci -6 alkyl)amino; Z is halo, trifluoromethyl, cyano, nitro, aryl, or heterocyclyl (including heteroaryl) which optionally bears 1 or 2 substituents, which may be the same or different, selected from halo, and C].
  • Z is a group of sub-formula (vi) -X 4 -R 18 (vi) where X 4 is selected from O, NR 19 , S, SO, SO 2 , OSO 2 , CO, C(O)O, OC(O), CON(R 19 ), N(R 19 )C0, SO 2 N(R 19 ), and N(R 19 )SO 2 , where each R 19 is independently selected from hydrogen or Ci ⁇ alkyl; and R 18 is selected from hydrogen, Ci -6 alkyl, aryl, or heterocyclyl (including heteroaryl) which optionally bears 1 or 2 substituents, which may be the same or different, selected from halo, C 1-6 alkyl, and C 1-6 alkoxy, and wherein any heterocyclyl group within R 18 optionally bears 1 or 2 oxo substituents;
  • R 4 is a group of sub-formula (iiib)
  • R 6 and R 8 are 5, 6, or 7-membered heterocyclic ring which is nitrogen-linked and the other is independently selected from:
  • X 2 is selected from O, NR 16 , S, SO, SO 2 , OSO 2 , CO 5 C(O)O, OC(O), CH(OR 16 ), CON(R 16 ), N(R 16 )C0, SON(R 16 ), N(R 16 )S0, SO 2 N(R 16 ), and N(R 16 )SO 2 , where each R 16 is independently selected from hydrogen or C 1-6 alkyl, R 14 is hydrogen, Cj -6 alkyl, trifluoromethyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl,
  • C 3-I2 carbocyclyl or a 4- to 8-membered mono or bicyclic heterocyclyl ring (including 5 or 6 membered heteroaryl rings) and wherein any aryl, C 3-J2 carbocyclyl, heterocyclyl (including heteroaryl) groups are optionally substituted on any available carbon atoms by oxo, halo, cyano, amino, C 1- 6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylcarbonyl, N-C 1-6 alkylamino, or N,N-diC 1-6 alkylamino and any nitrogen atoms present in the heterocyclyl moieties may, depending upon valency considerations, be substituted by a group selected from hydrogen, C 1-6 alkyl or C 1-6 alkylcarbonyl, and where any sulphur atoms may be optionally oxidised to a sulphur oxide; (c) a group of sub-formula (v)
  • X 3 is a direct bond or is selected from O, NR 17 , S, SO, SO 2 , OSO 2 ,
  • R 17 is independently selected from hydrogen or C 1-6 alkyl;
  • R 15 is a Ci -6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, arylene, C 3-12 carbocyclyl, heterocyclyl (including heteroaryl), any of which may be optionally substituted by one or more groups selected from halo, hydroxy,
  • Z is halo, trifiuoromethyl, cyano, nitro, aryl, or heterocyclyl (including heteroaryl) which optionally bears 1 or 2 substituents, which may be the same or different, selected from halo, C 1-6 alkyl and C 1-6 alkoxy and wherein any heterocyclyl group within Z optionally bears 1 or 2 oxo substituents, or ,
  • Z is a group of sub-formula (vi)
  • R 19 is independently selected from hydrogen or C 1-6 alkyl; and R 18 is selected from hydrogen, C 1-6 alkyl, aryl, or heterocyclyl (including heteroaryl) which optionally bears 1 or 2 substituents, which may be the same or different, selected from halo, C 1-6 alkyl, and Ci -6 alkoxy, and wherein any heterocyclyl group within R optionally bears 1 or 2 oxo substituents; 30.
  • R 4 is a group of sub-formula (iiib)
  • R 6 and R 8 are a 5 or 6-membered nitrogen-linked heterocyclic ring and the other is independently selected from:
  • X 2 is selected from O, NR 16 , S 5 SO 5 SO 2 , OSO 23 CO 5 C(O)O, OC(O), CH(OR 16 ), CON(R 16 ), N(R 16 )C0, SON(R 16 ), N(R 16 )SO, SO 2 N(R 16 ), and N(R 16 )SO 2 , where each R 16 is independently selected from hydrogen or C 1-6 alkyl, R 14 is hydrogen, Ci -6 alkyl, trifluoromethyl, C 2-8 alkenyl, C 2 . 8 alkynyl, aryl,
  • C 3-J2 carbocyclyl or a 4- to 8-membered mono or bicyclic heterocyclyl ring (including 5 or 6 membered heteroaryl rings) and wherein any aryl, C 3- I 2 carbocyclyl, heterocyclyl (including heteroaryl) groups are optionally substituted on any available carbon atoms by oxo, halo, cyano, amino, C 1- ⁇ alkyl, hydroxyCi -6 alkyl, Ci.
  • Ci -6 alkylcarbonyl, N-C 1-6 alkylamino, or N,N-diCi -6 alkylamino and any nitrogen atoms present in the heterocyclyl moieties may, depending upon valency considerations, be substituted by a group selected from hydrogen, Ci -6 alkyl or C 1-6 alkylcarbonyl, and where any sulphur atoms may be optionally oxidised to a sulphur oxide; (c) a group of sub-formula (v) is
  • X 3 is a direct bond or is selected from O, NR 17 , S 5 SO 9 SO 2 , OSO 2 ,
  • R 17 is independently selected from hydrogen or C 1-6 alkyl;
  • R 15 is a C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, arylene, C 3-12 carbocyclyl, heterocyclyl (including heteroaryl), any of which may be optionally substituted by one or more groups selected from halo, hydroxy,
  • Z is halo, trifluoromethyl, cyano, nitro, aryl, or heterocyclyl (including heteroaryl) which optionally bears 1 or 2 substituents, which may be the same or different, selected from halo, Ci_ 6 alkyl and Ci -6 alkoxy and wherein any heterocyclyl group within Z optionally bears 1 or 2 oxo substituents, or
  • Z is a group of sub-formula (vi)
  • X 4 is selected from O, NR 19 , S, SO, SO 2 , OSO 2 , CO, C(O)O, OC(O), CON(R 19 ), N(R 19 )C0, SO 2 N(R 19 ), and N(R 19 )SO 2 , where each R 19 is independently selected from hydrogen or C 1-6 alkyl; and R 18 is selected from hydrogen, C 1-6 alkyl, aryl, or heterocyclyl (including heteroaryl) which optionally bears 1 or 2 substituents, which may be the same or different, selected from halo, Ci -6 alkyl, and C 1-6 alkoxy, and wherein any heterocyclyl group within R 18 optionally bears 1 or 2 oxo substituents;
  • R >4 is a group of sub-formula (iiib)
  • R 6 and R 8 are morpholin-4-yl and the other is independently selected from:
  • X 2 is selected from O, NR 16 , S, SO, SO 2 , OSO 2 , CO, C(O)O, OC(O), CH(OR 16 ), CON(R 16 ), N(R 16 )C0, SON(R 16 ), N(R 16 )SO, SO 2 N(R 16 ), and N(R 16 )SO 2 , where each R 16 is independently selected from hydrogen or C 1-6 alkyl,
  • R 14 is hydrogen, Ci -6 alkyl, trifluoromethyl, C 2- salkenyl, C 2-8 alkynyl, aryl, C 3-12 carbocyclyl, or a 4- to 8-membered mono or bicyclic heterocyclyl ring (including 5 or 6 membered heteroaryl rings) and wherein any aryl, C 3-12 carbocyclyl, heterocyclyl (including heteroaryl) groups are optionally substituted on any available carbon atoms by oxo, halo, cyano, amino, C 1- 6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, C ⁇ alkylcarbonyl, N-C 1-6 alkylamino, or N,N-diCi -6 alkylamino and any nitrogen atoms present in the heterocyclyl moieties may, depending upon valency considerations, be substituted by a group selected from hydrogen, Ci -6 alkyl or Ci -6 alkylcarbonyl, and where any
  • X 3 is a direct bond or is selected from O, NR 17 , S, SO, SO 2 , OSO 2 , CO, C(O)O, OC(O), CON(R 17 ), N(R 17 )C0, SO 2 N(R 17 ), and N(R 17 )SO 2 , where each R 17 is independently selected from hydrogen or C h alky!;
  • R 15 is a C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, arylene, C 3-12 carbocyclyl, heterocyclyl (including heteroaiyl), any of which may be optionally substituted by one or more groups selected from halo, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, cyano, amino, Ci.
  • Z is halo, trifluoromethyl, cyano, nitro, aryl, or heterocyclyl (including heteroaryl) which optionally bears 1 or 2 substituents, which may be the same or different, selected from halo, Ci -6 alkyl and C 1-6 alkoxy and wherein any heterocyclyl group within Z optionally bears 1 or 2 oxo substituents, or Z is a group of sub-formula (vi) -X 4 -R 18 (vi) where X 4 is selected from O, NR 19 , S, SO, SO 2 , OSO 2 , CO, C(O)O, OC(O), CON(R 19 ), N(R 19 )CO, SO 2 N(R 19 ), and N(R 19 )SO 2 , where each R 19 is independently selected from hydrogen or C 1-6 alkyl; and R 18 is selected from hydrogen, C 1-6 alkyl, aryl
  • R 4 is a group of sub-formula (iiib)
  • R 6 and R 8 are morpholin-4yl and the other is independently selected from:
  • X 2 is selected from O, NR 16 , S, SO, SO 2 , OSO 2 , CO, CON(R 16 ), N(R 16 )C0, SON(R 16 ), N(R 16 )SO, SO 2 N(R 16 ), and N(R 16 )SO 2 , where each R 16 is independently selected from hydrogen or Ci ⁇ alkyl, R 14 is hydrogen, or C 1-4 alkyl;
  • R 4 is a group of sub-formula (iiib)
  • R 6 and R 8 are 5 or 6-membered nitrogen-linked heterocyclylic rings
  • R 4 is a group of sub-formula (iiib)
  • R 6 and R 8 are morpholin-4-yl.
  • R 1 is hydrogen or an alkyl group as defined in any one of paragraphs (9) to (12) above (particularly methyl) and ring A, R 3 , n, and R 4 have any one of the definitions set out herein.
  • R 1 is an alkyl group as defined in any one of paragraphs (14) to (16) above, particularly a methyl group, and ring A, R 3 , n, and R 4 have any one of the definitions set out herein.
  • R 4 is a sub-group of formula (iiib) as defined in any one of paragraphs (29) to (34) above, and particularly a sub-group of formula (iiib) as defined in any one of paragraphs (33) to (34) above, and ring A, R 1 , R 3 , and n have any one of the definitions set out herein.
  • R 1 is an alkyl group as defined in any one of paragraphs (14) to (16) above, particularly a methyl group,
  • R 4 is a sub-group of formula (iiib) as defined in any one of paragraphs (29) to (34) above, and particularly a sub-group of formula (iiib) as defined in any one of paragraphs (33) to (34) above, and ring A, R 1 , R 3 , and n have any one of the definitions set out herein.
  • R 1 is hydrogen
  • a particular group of compounds of formula I are subject to the proviso that if Ring A, together with the phenyl ring to which it is attached, form an indazol-4-yl group, then R 1 is a C 1-6 alkyl group, particularly a C 1-2 alkyl group, and most particularly methyl.
  • R 1 is a C 1-6 alkyl group, particularly a C 1-2 alkyl group, and most particularly methyl.
  • a further group of compounds of formula I are subject to the proviso that, if Ring A, together with the phenyl ring to which it is attached, form an indazol-4-yl group, then R 1 is a C 1-6 alkyl group, particularly a C 1-2 alkyl group, and most particularly methyl.
  • a further group of compounds of formula I are subject to the proviso that, if Ring A, together with the phenyl ring to which it is attached, form an indazol-4-yl group, then R 1 is a C 1-6 al
  • R 1 is a C 1-6 alkyl group, particularly a C 1-2 alkyl group and most particularly methyl.
  • a particular group of compounds of formula I are subject to the proviso that, if Ring A, together with the phenyl ring to which it is attached, form an indazol-4-yl group, then R 1 is a C 1-6 alkyl group, particularly a Ci -2 alkyl group, and most particularly methyl, and R 4 is a sub-group of formula (iiib) as defined in any one of paragraphs (29) to (34) above, and in particular a sub-group of formula (iiib) as defined in any one of paragraphs (33) to (34) above.
  • R 1 is a Ci -6 alkyl group, which is optionally substituted with one or more substituents selected from cyano, -OR 2 , -NR 2a R 2b , where R 2 , R 2a and R 2b are selected from hydrogen or Ci -2 alkyl; and R 3 , n, R 22 , and R 4 have any one of the definitions set out herein.
  • R 1 is as defined in any one of paragraphs (14) to (16) above,
  • R 22 is as defined in any one of paragraphs (1) to (8) above,
  • R 3 if present, is as defined in any one of paragraphs (21) to (25) above,
  • R is suitably an alkyl group as defined in any one of paragraphs (14) to (16) above.
  • R 1 is methyl.
  • n is suitably 0 or 1, particularly 0.
  • R 22 is suitably hydrogen, halo, or Ci -2 alkyl, and is especially hydrogen, methyl or chloro.
  • R 4 is suitably a phenyl group as defined in any one of paragraphs (26) to (34) above, and particularly a phenyl group as defined in any one of paragraphs (29) to (34) above, and most particularly a phenyl group as defined in either of paragraphs (33) or (34) above.
  • R 1 is an alkyl group as defined in any one of paragraphs (14) to (16) above;
  • R 22 is hydrogen, halo, or Ci -2 alkyl
  • R 4 is a phenyl group as defined in any one of paragraphs (29) to (34) above.
  • R 4 is a phenyl group as defined in any one of paragraphs (29) to (34) above.
  • R 1 is methyl
  • R 22 is hydrogen, methyl or chloro
  • R 4 is a phenyl group as defined in either of paragraphs (33) or (34) above.
  • a further particular group of compounds of the invention have the general structural formula (IE) shown below
  • R 1 , R 22 , R 3 , n, and R 4 have any of the definitions set out herein.
  • IE compound of formula
  • R 1 is as defined in any one of paragraphs (9) to (16) above,
  • R 22 is as defined in any one of paragraphs (1) to (8) above,
  • R 3 if present, is as defined in any one of paragraphs (21) to (25) above,
  • R 1 is suitably hydrogen or C 1-2 alkyl, particularly methyl. In a particular group of compounds of formula (IE), R 1 is methyl.
  • n is suitably 0 or 1, particularly 0.
  • R 22 is suitably hydrogen, halo, or Ci -2 alkyl, and is especially hydrogen, methyl or chloro.
  • R 4 is suitably a phenyl group as defined in any one of paragraphs (26) to (34) above, and particularly a phenyl group as defined in any one of paragraphs (29) to (34) above, and most particularly a phenyl group as defined in either of paragraphs (33) or (34) above.
  • R 1 is hydrogen or an alkyl group as defined in any one of paragraphs (14) to (16) above;
  • R 22 is hydrogen, halo, or C 1-2 alkyl
  • R 4 is a phenyl group as defined in any one of paragraphs (29) to (34) above.
  • IE formula
  • R 1 is methyl
  • R 22 is hydrogen, methyl or chloro
  • R 4 is a phenyl group as defined in either of paragraphs (33) or (34) above.
  • R 1 , R 22 , R 3 , n, and R 4 have any of the definitions set out herein.
  • R 1 , R 22 , R 3 , n, and R 4 have any of the definitions set out herein.
  • R 1 is as defined in any one of paragraphs (9) to (16) above,
  • R 22 is as defined in any one of paragraphs (1) to (8) above,
  • R 4 is as defined in any one of paragraphs (26) to (34) above.
  • R 1 is suitably hydrogen or Ci -2 alkyl, particularly methyl. In a particular group of compounds of formula (IE), R 1 is methyl. In compounds of formula (IF), n is suitably 0 or 1, particularly 0.
  • R 22 is suitably hydrogen, halo, or C 1-2 alkyl, and is especially hydrogen, methyl or chloro.
  • R 4 is suitably a phenyl group as defined in any one of paragraphs (26) to (34) above, and particularly a phenyl group as defined in any one of paragraphs (29) to (34) above, and most particularly a phenyl group as defined in either of paragraphs (33) or (34) above.
  • R 1 is hydrogen or an alkyl group as defined in any one of paragraphs (14) to (16) above; • n is O;
  • R is hydrogen, halo, or Ci -2 alkyl
  • R 4 is a phenyl group as defined in any one of paragraphs (29) to (34) above.
  • R j 22 is hydrogen, methyl or chloro
  • R >4 is a phenyl group as defined in either of paragraphs (33) or (34) above.
  • a further particular group of compounds of the invention have the general structural formula (IG) shown below
  • R 1 is as defined in any one of paragraphs (9) to (16) above,
  • R is as defined in any one of paragraphs (1) to (8) above,
  • n is as defined in any one of paragraphs (17) to (20) above, and
  • R 4 is as defined in any one of paragraphs (26) to (34) above.
  • R 1 is suitably hydrogen or C 1-2 alkyl, particularly methyl. In a particular group of compounds of formula (IE), R 1 is methyl.
  • n is suitably 0 or 1 , particularly 0.
  • R 22 is suitably hydrogen, halo, or Ci -2 alkyl, and is especially hydrogen, methyl or chloro.
  • R 4 is suitably a phenyl group as defined in any one of paragraphs (26) to (34) above, and particularly a phenyl group as defined in any one of paragraphs (29) to (34) above, and most particularly a phenyl group as defined in either of paragraphs (33) or (34) above.
  • R 1 is hydrogen or an alkyl group as defined in any one of paragraphs (14) to (16) above;
  • R 22 is hydrogen, halo, or Ci -2 alkyl
  • R 4 is a phenyl group as defined in any one of paragraphs (29) to (34) above.
  • IG is a phenyl group as defined in any one of paragraphs (29) to (34) above.
  • R 1 is methyl
  • R 22 is hydrogen, methyl or chloro
  • R is a phenyl group as defined in either of paragraphs (33) or (34) above.
  • Particular compounds of the invention include any one of the following:
  • N ⁇ 4 (5-chloro-l,3-benzodioxol-4-yl)-N ⁇ 2 ⁇ -(3-fiuorophenyl) ⁇ yrimidine-2,4-diamine; N ⁇ 4 — (5-chloro-l,3-benzodioxol-4-yl)-N ⁇ 2— (4-fluorophenyl) ⁇ yrimidine-2,4-diamine;
  • N ⁇ 4 (5-chloro-l,3-benzodioxol-4-yl)-N ⁇ 2 ⁇ -[4-(pyridin-2-ylmethoxy)phenyl]pyrimidine- 2,4-diamine; l-[4-( ⁇ 4-[(5-chloro-l,3-benzodioxol-4-yl)aniino]pyrimidin-2-yl ⁇ amino)plienyl]-N- methylmethanesulfonamide;
  • a suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation
  • a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxye
  • the compounds of the invention may be administered in the form of a pro-drug that is a compound that is broken down in the human or animal body to release a compound of the invention.
  • a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
  • a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached.
  • Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula (I) and in vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula (I).
  • the present invention includes those compounds of the Formula (I) as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula (I) that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula (I) may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • Various forms of pro-drug have been described, for example in the following documents: - a) Methods in Enzymology. Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.
  • Bundgaard Chapter 5 "Design and Application of Pro-drugs", by H. Bundgaard p. 113- 191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews. 8, 1 -38 (1992); e) H. Bundgaard, et ah, Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et a!., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) that possesses a carboxy group is, for example, an in vivo cleavable ester thereof.
  • An in vivo cleavable ester of a compound of the Formula (I) containing a carboxy group is, for example, a pharmaceutically-acceptable ester, which is cleaved in the human or animal body to produce the parent acid.
  • Suitable pharmaceutically-acceptable esters for carboxy include (l-6C)alkyl esters such as methyl, ethyl and tert-butyl, (l-6C)alkoxymethyl esters such as methoxymethyl esters, (l- ⁇ C)alkaiioyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(l-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-oxo-l,3- dioxolenylmethyl esters such as 5-methyl-2-oxo-l,3-dioxolen-4-ylmethyl esters and (1- 6C)alkoxycarbonyloxy-(l-6C)alkyl esters such as methoxycarbonyloxymethyl and 1 -methoxycarbonyloxy ethyl
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of the Formula (I) containing a hydroxy group is, for example, a pharmaceutically-acceptable ester or ether, which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • ester forming groups for a hydroxy group include (1- 10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (l-lOC)alkoxycarbonyl groups such as ethoxycarbonyl, 7V,iV-[di-(l- 4C)alkyl]carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • (1- 10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups
  • (l-lOC)alkoxycarbonyl groups such as ethoxycarbonyl, 7V,iV-[di-(l- 4C)alkyl]carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, iV,iV-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(l-4C)alkylpiperazin-l-ylmethyl.
  • Suitable pharmaceutically-acceptable ether forming groups for a hydroxy group include ⁇ -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically-acceptable amides from an amino group include, for example an amide formed with (l-lOC)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(l -4C)alkylpiperazin- 1 -ylmethyl.
  • the in vivo effects of a compound of the Formula (I) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula (I). As stated hereinbefore, the in vivo effects of a compound of the Formula (I) may also be exerted by way of metabolism of a precursor compound (a pro-drug).
  • optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • R 1 , R 3 and n are as defined in relation to formula (I) provided that any functional groups are optionally protected. Thereafter, any protecting groups can be removed using conventional methods, and if required, the compound of formula (I) can be converted to a different compound of formula (I) or a salt, again using conventional chemical methods.
  • Suitable leaving groups L are halo such as chloro.
  • the reaction is suitably carried out in an organic solvent such as a Ci -6 alkanol, for instance, n-butanol, dimethylamine (DMA), or N-methylpyrrolidine (NMP) or mixtures thereof.
  • An acid, in particular, and inorganic acid such as hydrochloric acid is suitably added to the reaction mixture.
  • the reaction is suitably conducted at elevated temperatures for example at from 80-150°C, conveniently at the reflux temperature of the solvent.
  • R 4 is as defined in relation to formula (I), with a halogenating agent such as phosphorus oxychloride.
  • a halogenating agent such as phosphorus oxychloride.
  • the reaction is conducted under reactions conditions appropriate to the halogenating agent employed. For instance, it may be conducted at elevated temperatures, for example of from 50- 100 0 C, in an organic solvent such as acetonitrile or dichloromethane (DCM).
  • DCM dichloromethane
  • reaction is suitably effected in an organic solvent such as diglyme, again at elevated temperatures, for example of from 120-180°C, and conveniently at the reflux temperature of the solvent.
  • organic solvent such as diglyme
  • compounds of formula (I) may be prepared by reaction a compound of formula (VII)
  • R 3 R 1 and n are as defined in relation to formula (I) provided that any functional groups can be optionally protected, and L is a leaving group as defined in relation to formula (II), with a compound of formula (VI) as defined above.
  • any protecting groups can be removed using conventional methods, and if required, the compound of formula (I) can be converted to a different compound of formula (I) or a salt, again using conventional chemical methods.
  • L and L 1 are leaving groups such as halogen, and in particular chloro.
  • the reaction is suitably effected in the presence of a strong base such as sodium hydride, in an organic solvent such as DMA.
  • a strong base such as sodium hydride
  • organic solvent such as DMA.
  • Depressed temperatures for example from -2O 0 C to 20 0 C, conveniently at about 0 0 C are suitably employed.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a base such as sodium hydroxide
  • a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
  • Compounds of the formula I can be converted into further compounds of the formula I using standard procedures conventional in the art.
  • Examples of the types of conversion reactions that may be used to convert a compound of formula (I) to a different compound of formula (I) include introduction of a substituent by means of an aromatic substitution reaction or of a nucleophilic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents.
  • the reagents and reaction conditions for such procedures are well known in the chemical art.
  • Particular examples of aromatic substitution reactions include the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halo group.
  • nucleophilic substitution reactions include the introduction of an alkoxy group or of a monoalkylamino group, a dialkyamino group or a N-containing heterocycle using standard conditions.
  • reduction reactions include the reduction of a carbonyl group to a hydroxy group with sodium borohydride or of a nitro group to an amino group by catalytic hydrogenation with a nickel catalyst or by treatment with iron in the presence of hydrochloric acid with heating.
  • the preparation of particular compounds of formula (I), such as compounds of formula (IA), (IB), (IC), (ID), (IE), (IF), and (IG), using the above-described methods form a further aspect of the invention.
  • a pharmaceutical composition which comprises a compound of the formula (I) and in particular a compound of formula (IA), (IB), (IC), (ID), (IE), (IF), and (IG), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
  • the composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
  • a sterile solution, suspension or emulsion for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the above compositions may be prepared in a conventional manner using conventional excipients.
  • the compound of formula (I) will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000 mg/m 2 body area of the animal, i.e. approximately 0.1-100 mg/kg, and this normally provides a therapeutically-effective dose.
  • a unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg of active ingredient.
  • Preferably a daily dose in the range of 1-50 mg/kg is employed.
  • the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the practitioner who is treating any particular patient may determine the optimum dosage.
  • This assay detects inhibitors of EphB4-mediated phosphorylation of a polypeptide substrate using AlphascreenTM luminescence detection technology. Briefly, recombinant EpliB4 was incubated with a biotinylated-polypeptide substrate (biotin-poly-GAT) in presence of magnesium- ATP. The reaction was stopped by addition of EDTA, together with streptavidin-coated donor beads which bind the biotin-substrate containing any phosphorylated tyrosine residues. Anti-phosphotyrosine antibodies present on acceptor beads bind to phosphorylated substrate, thus bringing the donor & acceptor beads into close proximity.
  • biotinylated-polypeptide substrate biotin-poly-GAT
  • streptavidin-coated donor beads which bind the biotin-substrate containing any phosphorylated tyrosine residues.
  • Anti-phosphotyrosine antibodies present on acceptor beads bind to phosphorylated substrate
  • each compound dilution was transferred to appropriate wells of low volume white 384- well assay plates (Greiner, Stroudwater Business Park, Stonehouse, Gloucestershire, GLlO 3SX, Cat No. 784075) in duplicate.
  • Each plate also contained control wells: maximum signal was created using wells containing 2 ⁇ l of 5% DMSO, and minimum signal corresponding to 100% inhibition were created using wells containing 2 ⁇ l of 0.5M EDTA (Sigma- Aldrich Company Ltd, Catalogue No. E7889).
  • each well of the assay plate contained; lO ⁇ l of assay mix containing final buffer (1OmM Tris, lOO ⁇ M EGTA,
  • reaction was then stopped by addition of 5 ⁇ l/well stop buffer (1OmM Tris, 495mM EDTA, lmg/ml BSA) containing 0.25ng each of AlphaScreen anti- phosphoTyrosine-100 acceptor beads and streptavidin-coated donor beads (Perkin Elmer, Catalogue No 6760620M).
  • stop buffer 1OmM Tris, 495mM EDTA, lmg/ml BSA
  • AlphaScreen anti- phosphoTyrosine-100 acceptor beads and streptavidin-coated donor beads Perkin Elmer, Catalogue No 6760620M.
  • the resulting assay signal was determined on the Perkin Elmer EnVision plate reader. The minimum value was subtracted from all values, and the signal plotted against compound concentration to generate IC 50 data.
  • This assay identifies inhibitors of cellular EphB4 by measuring a decrease in phosphorylation of EphB4 following treatment of cells with compound.
  • the endpoint assay used a sandwich ELISA to detect EphB4 phosphorylation status. Briefly, Myc- tagged EphB4 from treated cell lysate was captured on the ELISA plate via an anti-c-Myc antibody. The phosphorylation status of captured EphB4 was then measured using a generic phosphotyrosine antibody conjugated to HRP via a colourimetric output catalysed by HRP, with level of EphB4 phosphorylation directly proportional to the colour intensity. Absorbance was measured spectrophotometrically at 450nm.
  • Full length human EphB4 (Swiss-Prot Ace. No. P54760) was cloned using standard techniques from cDNA prepared from HUVEC using RT-PCR. The cDNA fragment was then sub-cloned into a pcDNA3.1 expression vector containing a Myc-His epitope tag to generate full-length EphB4 containing a Myc-His tag at the C-terminus (Invitrogen Ltd. Paisley, UK). CHO-Kl cells (LGC Promochem, Teddington, Middlesex, UK, Catalogue No. CCL-61) were maintained in HAM's F12 medium (Sigma-Aldrich Company Ltd, Gillingham, Dorset SP8 4XT, Catalogue No.
  • EphB4-CHO CHO- Kl cells were engineered to stably express the EphB4-Myc-His construct using standard stable transfection techniques, to generate cells hereafter termed EphB4-CHO.
  • EphB4-CHO cells were seeded into each well of Costar 96- well tissue-culture plate (Fisher Scientific UK, Loughborough, Leicestershire, UK., Catalogue No. 3598) and cultured overnight in full media. On day 2, the cells were incubated overnight in 90 ⁇ l/ well of media containing 0.1% Hyclone stripped-serum (Fisher Scientific UK, Catalogue No. SH30068.02). Test compounds were prepared as 1OmM stock solutions in DMSO (Sigma- Aldrich Company Ltd, Gillingham, Dorset SP8 4XT Catalogue No.154938) and serially diluted with serum-free media to give a range of test concentrations at 1Ox the required final concentration.
  • Recombinant ephrin-B2-Fc (R&D Systems, Abingdon Science Park, Abingdon, Oxon OX14 3NB UK, Catalogue No. 496-EB), a Fc-tagged form of the cognate ligand for EphB4, was pre-clustered at a concentration of 3 ⁇ g/ml with 0.3 ⁇ g/ml anti-human IgG, Fc fragment specific (Jackson ImmunoResearch Labs, Northfield Business Park, Soham, Cambridgeshire, UK CB7 5UE, Catalogue No. 109-005-008) in serum-free media for 30 minutes at 4°C with occasional mixing.
  • ELISA plates were washed four times with PBS/0.05% Tween-20 and incubated for 1 hour at room temperature with lOO ⁇ l/well HRP-conjugated 4G10 anti- phosphotyrosine antibody (Upstate, Dundee Technology Park, Dundee, UK, DD2 1 SW, Catalogue No. 16-105) diluted 1 :6000 in 3% Top Block.
  • ELISA plates were washed four times with PBS/0.05% Tween-20 and developed with lOO ⁇ l/well TMB substrate (Sigma- Aldrich Company Ltd, Catalogue No. T0440). The reaction was stopped after 15 minutes with the addition of 25 ⁇ l/well 2M sulphuric acid. The absorbances were determined at 450nm using the Tecan SpectraFluor Plus. The minimum value was subtracted from all values, and the signal plotted against compound concentration to generate IC 50 data.
  • test compounds to inhibit the phosphorylation of a tyrosine containing polypeptide substrate by the enzyme c-Src kinase was assessed using a conventional ELISA assay with a colorimetric endpoint.
  • Matrix 384-well plates (Matrix, Brooke Park, Wilmslow, Cheshire,
  • SK9 3LP, UK, Catalogue No. 4311 were coated overnight at 4°C with 40 ⁇ l of lOug/ml stock of synthetic polyamino acid pEAY substrate (Sigma- Aldrich Company Ltd, Gillingham, Dorset, SP8 4XT, UK, Catalogue No. P3899) in phosphate buffered saline (PBS). Immediately prior to the assay, the plates were washed with lOO ⁇ l/well of PBS containing Tween-20 and then with 5OmM HEPES pH7.4.
  • Test compounds were prepared as 1OmM stock solutions in DMSO (Sigma- Aldrich Company Ltd, Gillingham, Dorset, SP8 4XT, UK, Catalogue No.154938) and serially diluted with 10% DMSO to give a range of test concentrations at 4x the required final concentration. A lO ⁇ l aliquot of each compound dilution was transferred to the appropriate ELISA wells in duplicate. Each plate also contained control wells: maximum signal was created using wells containing lO ⁇ l of 10% DMSO, and minimum signal corresponding to 100% inhibition were created using wells containing lO ⁇ l of 0.5M EDTA (Sigma-Aldrich Company Ltd, Catalogue No. E7889).
  • Compounds of the invention were active in the above assays, for instance, generally showing IC 50 values of less than lOO ⁇ M in Assay A and Assay B. Preferred compounds of the invention generally showing IC 5O values of less than 30 ⁇ M in Assay A and Assay B.
  • Compound 59 of the Examples showed an IC 5O of 0.46 ⁇ M in assay A, an IC 50 of 1.25 ⁇ M in assay B, an IC 5O of 0.33 ⁇ M in assay C.
  • Further illustrative IC 50 values obtained using Assay B for a selection of the compounds exemplified in the present application are shown in Table A below.
  • the compounds of the present invention are expected to be useful in the treatment of diseases or medical conditions mediated alone or in part by EphB4 enzyme activity, i.e. the compounds may be used to produce an EphB4 inhibitory effect in a warm-blooded animal in need of such treatment.
  • the compounds of the present invention provide a method for treating the proliferation of malignant cells characterised by inhibition of the EphB4 enzyme, i.e. the compounds may be used to produce an antiproliferative effect mediated alone or in part by the inhibition of EphB4.
  • certain compounds of the invention may also be active against the EphA2 or Src kinase enzymes, i.e. the compounds may also be used to produce an EphA2 and Src kinase inhibitory effect in a warm-blooded animal in need of such treatment.
  • the compounds of the present invention provide a method for treating the proliferation of malignant cells characterised by inhibition of EphB4, EphA2 or Src enzymes, i.e. the compounds may be used to produce an antiproliferative effect mediated alone or in part by the inhibition of EphB4, EphA2 or Src kinase.
  • R 1 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted by one or more substituent groups selected from cyano, nitro, -OR 2 , -NR 2a R 2b , -C(O)NR 2a R 2b , or -N(R 2a )C(O)R 2 , halo or haloC )-4 alkyl, where R 2 , R 2a and R 2b are selected from hydrogen or C 1-6 alkyl such as methyl, or R 2a and R 2b together with the nitrogen atom to which they are attached may form a 5 or 6-membered heterocyclic ring, which optionally contains an additional heteroatom selected from N, O or S; ring A is fused 5 or 6-membered carbocyclic or heterocyclic ring, which is saturated or unsaturated, and is optionally substituted on any available carbon
  • each group R 3 is independently selected from halo, trifluoromethyl, cyano, nitro or a group of sub-formula (i) :
  • X 1 is selected from a direct bond or O, S, SO, SO 2 , OSO 2 , NR 13 , CO, CH(OR 13 ), CONR 13 , N(R l3 )CO, SO 2 N(R 13 ), N(R 13 )SO 2 , C(R 13 ) 2 O, C(R 13 ) 2 S, C(R 13 ) 2 N(R 13 ) and N(R 13 )C(R 13 ) 2 , wherein R 13 is hydrogen or C 1-6 alkyl and R 11 is selected from hydrogen, Ci -6 alkyl, C 2- salkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, aryl or heterocyclyl, C 3- scycloalkylC 1-6 alkyl, arylCi -6 alkyl or heterocyclylCi- ⁇ alkyl, any of which may be optionally substituted with one or more groups selected from halo, trifluor
  • R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from:
  • X 2 is selected from O, NR 16 , S, SO, SO 2 , OSO 2 , CO, C(O)O, OC(O), CH(OR 16 ), CON(R 16 ), N(R 16 )C0, -N(R 16 )C(O)N(R 16 )-, -N(R 16 )C(0)0-, SON(R 16 ), N(R 16 )SO, SO 2 N(R 16 ), N(R 16 )SO 2 , C(R 16 ) 2 O, C(R 16 ) 2 S and N(R 16 )C(R 16 ) 2 , where each R 16 is independently selected from hydrogen or Ci -6 alkyl,
  • R 14 is hydrogen, C 1-6 alkyl, trifluoromethyl, C 2-8 alkenyl, C 2 . 8 alkynyl, aryl, C 3-12 carbocyclyl, aryl-C 1-6 alkyl, or a 4- to 8-membered mono or bicyclic heterocyclyl ring (including 5 or 6 membered heteroaryl rings) or 4- to 8-membered mono or bicyclic heterocyclyl-C 1-6 alkyl groups (including 5 or 6 membered heteroaryl- C 1-6 alkyl groups) and wherein any aryl, C 3-12 carbocyclyl, aryl-C 1-6 alkyl, heterocyclyl (including heteroaryl), heterocyclyl-C 1-6 alkyl (including heteroaryl- C 1-6 alkyl) groups are optionally substituted on any available carbon atoms by oxo, halo, cyano, amino, C 1-6 alkyl, hydroxyCi -6 alkyl, C 1-6 alkoxy
  • X 3 is a direct bond or is selected from O, NR 17 , S, SO, SO 2 , OSO 2 , CO, C(O)O, OC(O), CH(OR 17 ), CON(R 17 ), N(R 17 )CO, -N(R 17 )C(O)N(R 17 )-,
  • R 17 is independently selected from hydrogen or C 1-6 alkyl
  • R 15 is a Ci -6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, arylene, C 3-I2 carbocyclyl, heterocyclyl (including heteroaryl), any of which may be optionally substituted by one or more groups selected from halo, hydroxy, Ci -6 alkyl, C 1-6 alkoxy, cyano, amino, Ci -6 alkylamino or di-(C 1-6 alkyl)amino;
  • Z is halo, trifluoromethyl, cyano, nitro, aryl, C 3-12 carbocyclyl or heterocyclyl (including heteroaryl) which optionally bears 1 or 2 substituents, which may be the same or different, selected from halo, Q ⁇ alkyl, C 2-8 alkenyl, C 2- salkynyl and C 1-6 alkoxy and wherein any heterocyclyl group within Z optionally bears 1 or 2 oxo substituents, or Z is a group of sub-formula (vi)
  • X 4 is selected from O, NR 19 , S, SO, SO 2 , OSO 2 , CO, C(O)O, OC(O), CH(OR 19 ), CON(R 19 ), N(R 19 )C0, SO 2 N(R 19 ), -N(R 19 )C(O)N(R 19 )-, -N(R 19 )C(0)0-
  • R 19 is independently selected from hydrogen or Ci -6 alkyl
  • R 18 is selected from hydrogen, Ci -6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 3-I2 carbocyclyl, aryl-Ci -6 alkyl, heterocyclyl (including heteroaryl) or heterocyclyl-Ci -6 alkyl (including heteroaryl- Ci -6 alkyl) which optionally bears 1 or 2 substituents, which may be the same or different, selected from halo, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl and Ci -6 alkoxy, and wherein any heterocyclyl group within R 18 optionally bears 1 or 2 oxo substituents; or (iv) R 5 and R 6 , R 6 and R 7
  • a compound of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG) or (IH), or a pharmaceutically acceptable salt thereof as defined hereinbefore in the manufacture of a medicament for use in the production of an EphB4 inhibitory effect in a warm-blooded animal such as man.
  • a method for producing an EphB4 inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG) or (IH), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • a method for producing an EphB4, EphA2 and Src kinase inhibitory effect inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula (I), (IA),
  • a method for producing an anti-angiogenic effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG) or (IH), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • a method of treating cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG) or (IH), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • a method of treating neuroblastomas, breast, liver, lung and colon cancer or leukemias in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG) or (IH), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • the anti-cancer treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.
  • the other component(s) of such conjoint treatment in addition to the anti-angiogenic treatment defined hereinbefore may be: surgery, radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti-tumour agents: (i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antituniour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin- C 5 dactinomycin and mithramycin
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbBl antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol.
  • inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as iV-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZDl 839), iV-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3- morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitors
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti- vascular endothelial cell growth factor antibody bevacizumab (AvastinTM) and VEGF receptor tyrosine kinase inhibitors such as 4-(4- bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6- methoxy-7-(3-pyrrolidin-l-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SUl 1248 (sunitinib; WO 01/60814), compounds such as those disclosed in International Patent Applications WO97/22596, WO
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRC A2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the inimunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • a pharmaceutical composition comprising a compound of the formula (I) as defined hereinbefore and an additional anti-tumour substance as defined hereinbefore for the conjoint treatment of cancer.
  • the size of the dose required for the therapeutic or prophylactic treatment of a particular cell-proliferation disease will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.
  • a unit dose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg is envisaged.
  • the compounds of formula (I) are envisaged.
  • (IA) 5 (IB) or (IC) and their pharmaceutically acceptable salts thereof are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of anti-angiogenic activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • reaction times that are given are not necessarily the minimum attainable;
  • Preparative HPLC was performed on Cl 8 reversed-phase silica, on a Phenomenex "Gemini" preparative reversed-phase column (5 microns silica, HOA, 21.1 mm diameter, 100 mm length) using decreasingly polar mixtures as eluent, for example decreasingly polar mixtures of water (containing 0.1% formic acid or 0.1% ammonia) as solvent A and acetonitrile as solvent B; either of the following preparative HPLC methods were used: Method A: a solvent gradient over 9.5 minutes, at 25mls per minute, from a 85:15 mixture of solvents A and B respectively to a 5:95 mixture of solvents A and B. Method B: a solvent gradient over 9.5 minutes, at 25mls per minute, from a 60:40 mixture of solvents A and B respectively to a 5:95 mixture of solvents A and B.
  • temperatures are given in degrees Celsius ( 0 C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18 to 25°C;
  • organic solutions were dried over anhydrous magnesium sulfate or anhydrous sodium sulfate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600 to 4000 Pascals; 4.5 to 30mmHg) with a bath temperature of up to 60°C;
  • chromatography means flash chromatography on silica gel; thin layer chromatography
  • NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 500 MHz using perdeuterio dimethyl sulfoxide (DMSOd 6 ) as solvent unless otherwise indicated; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad;
  • (x) mass spectra were run with an electron energy of 70 electron volts in the chemical ionization (CI) mode using a direct exposure probe; where indicated ionization was effected by electron impact (EI), fast atom bombardment (FAB) or electrospray (ESP); values for m/z are given; generally, only ions which indicate the parent mass are reported; and unless otherwise stated, the mass ion quoted is (MH) + which refers to the protonated mass ion; reference to M + is to the mass ion generated by loss of an electron; and reference to M-H is to the mass ion generated by loss of a proton; (xi) unless stated otherwise compounds containing an asymmetrically substituted carbon and/or sulfur atom have not been resolved;
  • EI electron impact
  • FAB fast atom bombardment
  • ESP electrospray
  • Wavelength 254 nm Injection volume 2.0-4.0 ml;
  • Example 1 The procedure described above in Example 1 was repeated using the appropriate aniline (which were sourced commercially or prepared as described in the Method section below). Thus were obtained the compounds described below in Table 1.
  • Example 7 The procedure described in Example 6 above was repeated using the appropriate aniline. Thus were obtained the compounds described below in Table 3.
  • Example 10 The procedure described in Example 10 (Final compounds) was repeated using the appropriate aniline and 2-chloro-N-(5-fluorobenzo[l,3]dioxol-4-yl)pyrimidin-4-amine. Thus were obtained the compounds described in Table 6 below.
  • Example 10 The procedure described in Example 10 (Final compounds) was repeated using N- benzo[l,3]dioxol-4-yl-2-chloro-pyrimidin-4-arnine and the appropriate aniline. Thus were obtained the compounds described in Table 7 below.
  • Example 10 The procedure described in Example 10 (Final compounds) was repeated using N- benzo[l,3]dioxol-4-yl-2-chloro-N-methyl-pyrimidin-4-amine and the appropriate aniline. Thus were obtained the compounds described in Table 8 below.
  • N-(2-methylsulfonylpyrimidin-4-yl)-lH-indazol-4-amine (2.4 g, 71%) as a solid.
  • Example 10 The procedure described in Example 10 (Final compounds) was repeated using N-(5- chlorobenzo [ 1 ,3] dioxol-4-yl)-N-(2-chloropyrimidin-4-yl)-N',N'-dimethyl-ethane- 1 ,2- diamine (20 mg, 0.06 mmol) and 3-methylsulfonylaniline hydrochloride (13 mg, 0.06 mmol) except that the mixture was heated for 3 hours.
  • m-Chloroperbenzoic acid (13.6 g, 70% strength, 55 mmol) was added portionwise to an ice-cooled solution of 4-chloro-N-(3-methylsulfanylphenyl)pyrimidin ⁇ 2-amine (6.6 g, 26.3 mmol) in DCM (250 ml). The mixture was stirred at room temperature for 1 hour. The mixture was washed with aqueous sodium dithionate, aqueous sodium bicarbonate, then brine.
  • Example 16 The procedure described in Example 16 was repeated using tert-butyl N-(3-amino-2- hydroxy-phenyl)carbamate [365 mg, 1.6 mmol; obtained from 2,6-dinitrophenol by hydrogenation with 10% palladium over charcoal in ethanol to obtain the 2,6- diaminophenol (quantitative) and treatment of di-tert-butyldicarbonate (3.2 g, 1 eq.) in THF (50 ml) and chromatography on silica gel (eluant: 4% EtOAc in DCM)] as the aniline. After cooling, the crude mixture was concentrated and treated with 50% TFA in DCM (10 ml) for 1 hour at room temperature.
  • Example 18 The procedure described in Example 18 was repeated using tert-butyl N-(2-amino-6- hydroxy-phenyl)carbamate (365 mg, 1.63 mmol, Astrazeneca, PCT Int. App. WO 2003053960 p 59 Ex. 3 starting material) as the aniline:
  • Methyl iodide (1 ml, 16.1 mmol) was added to a mixture of l-benzyl-N-(2- methylsulfanylpyrimidm-4-yl)indazol-4-amine (5.6 g, 16.1 mmol) and cesium carbonate (10.5 g, 32.3 mmol) in acetonitrile (60 ml). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with acetonitrile and the solids were filtered off.
  • N-methyl-N-(2- methylsulfanylpyrimidin-4-yl)-lH-indazol-4-amine (3.1 g, 83%) as a white solid.
  • N-methyl-N-(2-methylsulfonylpyrimidin-4-yl)-lH-indazol-4-amine 2.4 g, 72%) as a white solid.
  • N-(2-chloropyrimidin-4-yl)benzooxazol-7-amine 600 mg, 2.44 mmol was reacted with methyl iodide according to the procedure of Example 10 (starting material (I)) to give N-
  • Methyl iodide (0.17 ml, 2.69 mmol) was added to a mixture of l-[(4- methoxyphenyl)methyl] -3 -methyl-N-(2-methylsulfany lpyrimidin-4-yl)indazol-4-amine ( 1 g, 2.56 mmol) and cesium carbonate (1.25 g, 3.84 mmol) in acetonitrile (6 ml). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with acetonitrile and the solids were filtered off.
  • Example 28 4-Chloro-N-(3,5-dimor ⁇ holin-4-ylphenyl)pyrimidin-2-amine (70 mg, 0.19 mmol) and the corresponding aniline (0.22 mmol) were dissolved in pentanol (1 ml). 4M HCl in dioxane (0.1 ml) was added. The reaction was heated at 100 0 C for 15 hours then cooled to room temperature and concentrated in vacuo.
  • Morpholine (12 ml) and l,3-difluoro-5-nitro-benzene (4 g) in DMSO (50 ml) were heated at 100 0 C for 4 days. The solution was cooled, poured into water and the resulting precipitate filtered and dried.
  • Methanesulfonyl chloride (62 ⁇ l) was added to a solution of 5-methylsulfonylbenzene-l,3- diamine (0.15 g - Method 8c) and pyridine (0.33 ml) in DCM (15 ml) and the reaction stirred for two hours at room temperature. The solution was washed with water, dried and concentrated and the residue purified by chromatography to give the title compound as a brown oil (45 mg, 21%); Mass Spectrum MH + 265.36.
  • Lithium aluminium hydride (0.48 ml, IM in THF) was added dropwise to ethyl 3-amino-5- morpholin-4-yl-benzoate (0.1 g - Method 8g) in THF (3 ml) and the mixture stirred overnight at room temperature.
  • Water (0.1 ml) was added, followed by aqueous sodium hydroxide (0.1 ml, IM), then magnesium sulfate (1 g) and diethyl ether (10 ml) added. The mixture was stirred at room temperature for 20 minutes then filtered and washed with ether.
  • Methanesulfonyl chloride (127 ⁇ l) was added to a solution of ethyl 3-amino-5-morpholin- 4-yl-benzoate (0.344 g - Method 8g) and pyridine (0.54 ml) in THF (3 ml) and the reaction stirred overnight at room temperature. The solution was concentrated in vacuo and the residue partitioned between IM HCl and diethyl ether.
  • Zinc powder 125 mg
  • zinc cyanide 560 mg
  • tris(dibenzylideneacetone)dipalladium(0) 290 mg
  • l,r-bis(diphenylphosphino)ferrocene 350 mg
  • 6-bromobenzo[l,3]dioxol-4-amine 1 g, prepared as described in WO2004005284
  • DIPEA 0.69 ml
  • n-Butyl Lithium (9.96 ml, 2.5M in hexanes) was added dropwise to a solution of tert-bx&yl N-(6-bromobenzo[l,3]dioxol-4-yl)carbamate (3 g, prepared as described in WO2004005284) in THF (60 ml) at -78 0 C and the mixture was stirred for 20 minutes.
  • DMF 0. ml
  • Saturated aqueous sodium bicarbonate solution 75 ml was added and the solution extracted with ethyl acetate, dried and concentrated.

Abstract

La présente invention concerne des composés de benzamide de Formule (I) ou un sel dérivé pharmaceutiquement acceptable, où R1, le cycle A, n, R3, et R4 sont tels qu’énoncés dans la description. La présente invention a aussi trait à des processus de préparation de tels composés, à des compositions pharmaceutiques les contenant et à leur utilisation dans la fabrication d’un médicament à utiliser comme agent antiproliférateur pour la prévention ou le traitement de tumeurs ou d’autres conditions prolifératrices qui sont sensibles à l’inhibition des kinases EphB4, et/ou EphA2 et/ou Src.
PCT/GB2007/000251 2006-01-26 2007-01-25 Derives de pyrimidine WO2007085833A2 (fr)

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JP2008551870A JP2009524632A (ja) 2006-01-26 2007-01-25 ピリミジン誘導体
BRPI0707284-8A BRPI0707284A2 (pt) 2006-01-26 2007-01-25 composto ou um sal farmaceuticamente aceitável do mesmo, composição farmacêutica, processo para preparar um composto, e , uso de um composto ou um sal farmaceuticamente aceitável do mesmo
AU2007209126A AU2007209126B2 (en) 2006-01-26 2007-01-25 Pyrimidine derivatives
NZ569763A NZ569763A (en) 2006-01-26 2007-01-25 N-(3,5-dimorpholinophenyl)-N'-(1H-indazol-4-yl)-N'-methyl-pyrimidine-2,4-diamine, compositions and uses thereof
US12/161,766 US20110046108A1 (en) 2006-01-26 2007-01-25 Pyrimidine derivatives
EP07700405A EP1981856A2 (fr) 2006-01-26 2007-01-25 Derives de pyrimidine
IL192610A IL192610A0 (en) 2006-01-26 2008-07-03 Pyrimidine derivatives
NO20083059A NO20083059L (no) 2006-01-26 2008-07-09 Pyrimidinderivater

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Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008049123A3 (fr) * 2006-10-19 2008-06-19 Rigel Pharmaceuticals Inc Compositions et procédés pour l'inhibition de la voie jak
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AR059218A1 (es) 2008-03-19
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US20110046108A1 (en) 2011-02-24
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AU2007209126A1 (en) 2007-08-02
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AU2007209126B2 (en) 2012-01-19
IL192610A0 (en) 2009-08-03
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